Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-YL)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

ABSTRACT

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/698,759, filed Apr. 3, 2013, which is the National Phase ofInternational Application No. PCT/US2011/036844, filed May 17, 2011,which designated the United States and was published in English, andfurther claims the benefit of both U.S. Provisional Application No.61/352,092, filed Jun. 7, 2010, and U.S. Provisional Application No.61/345,363, filed May 17, 2010. The foregoing related applications, intheir entirety, are incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to crystalline forms of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate and compositions, methods of manufacture andtherapeutic uses thereof.

BACKGROUND OF THE INVENTION

The endogenous neurotransmitter acetylcholine (Ach) mediates diversephysiological functions in the peripheral and central nervous systems(CNS) via muscarinic and nicotinic subclasses of acetylcholine receptors(AChRs). The nicotinic acetylcholine receptors (nAChRs) are ligand-gatedcell surface ion channels that are selectively activated by the naturalproduct nicotine. The diverse molecular subtypes or variants ofnicotinic acetylcholine receptor are based on the pentameric structureof the receptor. The nAChR subtypes are formed from diverse pentamericcombinations of nine molecularly distinct alpha subunits and fourmolecularly distinct beta subunits. A particularly interesting moleculartarget for therapeutic intervention is the alpha-7 nicotinic receptorsubtype, which is comprised of five alpha-7 monomeric subunits. Thus,agonists which are selective for the alpha-7 receptor have potential totreat a range of diseases. Alpha-7 agonists are expected to beespecially useful for the treatment of CNS disorders associated withcognitive deficits. This expectation is based on beneficial effects ofalpha-7 receptor activation on cognition, learning and memory. At thesame time, selective alpha-7 agonists are expected to cause fewer orless severe undesirable side effects, e.g. nausea, vomiting,tachycardia, which are mediated by the activation of certain othernicotinic receptor subtypes as for example by the non-selective agonistnicotine.

As such, there is a need for additional selective alpha-7 agonists forthe treatment of CNS disorders associated with cognitive deficits.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to novel crystallinecompounds for use in the treatment of CNS disorders associated withcognitive deficits. In particular, the invention provides crystallineforms, i.e., Form I and Form II, of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate having the following formula.

The invention further provides (a) pharmaceutical compositionscomprising one of the crystalline forms, (b) methods for the treatmentand/or prophylaxis of a condition in which administration of an α7nicotinic receptor agonist may be expected to be therapeutic using oneof the crystalline forms, and (c) methods of manufacturing one of thecrystalline forms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a phase diagram for Form I and Form II.

FIG. 2 depicts an X-ray powder diffraction (XRPD) spectrum for Form X.

FIG. 3 is a graph depicting the relationship between water activity andvolume fraction of water in acetonitrile/water systems at varioustemperatures.

FIG. 4 depicts a diagram of Form I and Form II using plots oftemperature against the value of water activity.

FIGS. 5A and 5B depict an X-ray powder diffraction (XRPD) spectrum forForm I.

FIGS. 6A and 6B depict an X-ray powder diffraction (XRPD) spectrum forForm II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention, including crystalline forms, methods, andpharmaceutical compositions will be described with reference to thefollowing definitions that, for convenience, are set forth below. Unlessotherwise specified, the below terms used herein are defined as follows.

I. Definitions

As used herein and unless otherwise specified, the term “crystal forms,”“crystalline forms” and related terms herein refer to solid forms thatare crystalline. Crystal forms include single-component crystal formsand multiple-component crystal forms, and include, but are not limitedto, polymorphs, solvates, hydrates, and/or other molecular complexes. Inone embodiment, the crystalline forms of the invention are monohydrates.In certain embodiments, a crystalline form is substantially pure,isolated or enriched in one crystalline form, and/or is substantiallyfree of amorphous forms and/or other crystal forms.

As used herein and unless otherwise specified, the term “crystalline”and related terms used herein, when used to describe a compound,substance, modification, material, component or product, unlessotherwise specified, mean that the compound, substance, modification,material, component or product is substantially crystalline asdetermined by X-ray diffraction. See, e.g., Remington: The Science andPractice of Pharmacy, 21.sup.st edition, Lippincott, Williams andWilkins, Baltimore, Md. (2005); The United States Pharmacopeia,23.sup.rd ed., 1843-1844 (1995).

Moreover, more detailed characterizations techniques for characterizingcrystal forms and amorphous forms may include, but are not limited to,thermal gravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray powder diffractometry (XRPD), single-crystal X-raydiffractometry, vibrational spectroscopy, e.g., infrared (IR) and Ramanspectroscopy, solid-state and solution nuclear magnetic resonance (NMR)spectroscopy, optical microscopy, hot stage optical microscopy, scanningelectron microscopy (SEM), electron crystallography and quantitativeanalysis, particle size analysis (PSA), surface area analysis,solubility measurements, dissolution measurements, elemental analysisand Karl Fischer analysis. Characteristic unit cell parameters may bedetermined using one or more techniques such as, but not limited to,X-ray diffraction and neutron diffraction, including single-crystaldiffraction and powder diffraction. Techniques useful for analyzingpowder diffraction data include profile refinement, such as Rietveldrefinement, which may be used, e.g., to analyze diffraction peaksassociated with a single phase in a sample comprising more than onesolid phase. Other methods useful for analyzing powder diffraction datainclude unit cell indexing, which allows one of skill in the art todetermine unit cell parameters from a sample comprising crystallinepowder. Furthermore, it would be understood by the ordinarily skilledartisan that identification of a crystal may be made using one of thesetechniques, e.g., X-ray powder diffractometry, and may be confirmedusing additional noted characterization techniques.

As used herein and unless otherwise specified, a sample comprising aparticular crystal form or amorphous form that is “substantially pure,”contains the particular crystal form or amorphous form in a chemicaland/or physical purity greater than about 75%, e.g., 80%, e.g., 85%,e.g., 90%, e.g., 91%, e.g., 92%, e.g., 93%, e.g., 94%, e.g., 95%, e.g.,96%, e.g., 97%, e.g., 98%, e.g., 99%, e.g., 99.25%., e.g., 99.50%.,e.g., 99.75%., e.g., 99.9%., e.g., 100% physically and/or chemicallypure. In certain embodiments, the particular crystal form or amorphousform is greater than about 90%, e.g., 91%, e.g., 92%, e.g., 93%, e.g.,94%, e.g., 95%, e.g., 96%, e.g., 97%, e.g., 98%, e.g., 99%, e.g.,99.25%., e.g., 99.50%., e.g., 99.75%., e.g., 99.9%., e.g., 100%physically and/or chemically pure. In particular embodiments, theparticular crystal form or amorphous form is greater than about 95%,e.g., 96%, e.g., 97%, e.g., 98%, e.g., 99%, e.g., 99.25%., e.g.,99.50%., e.g., 99.75%., e.g., 99.9%., e.g., 100% physically and/orchemically pure. In specific embodiments, the particular crystal form oramorphous form is greater than about 99%, e.g., 99.25%., e.g., 99.50%.,e.g., 99.75%., e.g., 99.9%., e.g., 100% physically and/or chemicallypure.

As used herein and unless otherwise specified, a sample or compositionthat is “substantially free” of one or more other solid forms and/orother chemical compounds means that the composition contains, inparticular embodiments, less than about 25%, e.g., 20%, e.g., 15%, e.g.,10%, e.g., 9%, e.g., 8%, e.g., 7%, e.g., 6%, e.g., 5%, e.g., 4%, e.g.,3%, e.g., 2%, e.g., 1%, e.g., 0.75%, e.g., 0.5%, e.g., 0.25%, e.g., or0.1% percent by weight of one or more amorphous forms and/or othercrystal forms. In certain embodiments, the composition contains lessthan 10%, e.g., 9%, e.g., 8%, e.g., 7%, e.g., 6%, e.g., 5%, e.g., 4%,e.g., 3%, e.g., 2%, e.g., 1%, e.g., 0.75%, e.g., 0.5%, e.g., 0.25%,e.g., or 0.1% percent by weight of one or more amorphous forms and/orother crystal forms. In particular embodiments, the composition containsless than 5%, e.g., 4%, e.g., 3%, e.g., 2%, e.g., 1%, e.g., 0.75%, e.g.,0.5%, e.g., 0.25%, e.g., or 0.1% percent by weight of one or moreamorphous forms and/or other crystal forms. In specific embodiments, thecomposition contains less than 1%, e.g., 0.75%, e.g., 0.5%, e.g., 0.25%,e.g., or 0.1% percent by weight of one or more amorphous forms and/orother crystal forms. In certain embodiments, a crystal form of asubstance may be physically and/or chemically pure.

As used herein and unless otherwise specified, the terms “polymorphs,”“polymorphic forms” and related terms herein, refer to two or morecrystal forms that consist essentially of the same molecule, molecules,and/or ions. Different polymorphs may have different physical propertiessuch as, e.g., melting temperature, heat of fusion, solubility,dissolution properties and/or vibrational spectra, as a result of thearrangement or conformation of the molecules and/or ions in the crystallattice. The differences in physical properties may affectpharmaceutical parameters such as storage stability, compressibility anddensity (important in formulation and product manufacturing), anddissolution rate (an important factor in bioavailability). Differencesin stability can result from changes in chemical reactivity (e.g.,differential oxidation, such that a dosage form discolors more rapidlywhen comprised of one polymorph than when comprised of anotherpolymorph) or mechanical changes (e.g., tablets crumble on storage as akinetically favored polymorph converts to thermodynamically more stablepolymorph) or both (e.g., tablets of one polymorph are more susceptibleto breakdown at high humidity). As a result of solubility/dissolutiondifferences, in the extreme case, some solid-state transitions mayresult in lack of potency or, at the other extreme, toxicity. Inaddition, the physical properties may be important in processing (e.g.,one polymorph might be more likely to form solvates or might bedifficult to filter and wash free of impurities, and particle shape andsize distribution might be different between polymorphs).

The terms “hydrate” and “hydrated” refer to a solvate wherein thesolvent comprises water. “Polymorphs of solvates” refers to theexistence of more than one crystal form for a particular solvatecomposition. Similarly, “polymorphs of hydrates” refers to the existenceof more than one crystal form for a particular hydrate composition.

As used herein and unless otherwise specified, the term “amorphous,”“amorphous form,” and related terms used herein, describe that thesubstance, component or product in question is not substantiallycrystalline as determined by X-ray diffraction. In particular, the term“amorphous form” describes a disordered solid form, i.e., a solid formlacking long range crystalline order. In certain embodiments, anamorphous form of a substance may be substantially free of otheramorphous forms and/or crystal forms. In other embodiments, an amorphousform of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphousforms and/or crystal forms on a weight basis. In certain embodiments, anamorphous form of a substance may be physically and/or chemically pure.In certain embodiments, an amorphous form of a substance be about 99%,98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/orchemically pure.

As used herein and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or a rangeof values which is provided to characterize a particular solid form,e.g., a specific temperature or temperature range, such as, e.g., thatdescribing a DSC or TGA thermal event, including, e.g., melting,dehydration, desolvation or glass transition events; a mass change, suchas, e.g., a mass change as a function of temperature or humidity; asolvent or water content, in terms of, e.g., mass or a percentage; or apeak position, such as, e.g., in analysis by IR or Raman spectroscopy orXRPD; indicate that the value or range of values may deviate to anextent deemed reasonable to one of ordinary skill in the art while stilldescribing the particular solid form. For example, in particularembodiments, the terms “about” and “approximately,” when used in thiscontext and unless otherwise specified, indicate that the numeric valueor range of values may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or rangeof values.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the advancement or worsening of the disease or disorderresulting from the administration of a compound of the invention to apatient with such a disease or disorder. In some embodiments, the termsrefer to the administration of a compound provided herein, with orwithout other additional active agents, after the onset of symptoms ofthe particular disease. The terms “treating”, “treatment”, or the like,as used herein covers the treatment of a disease-state in a subject,e.g., a mammal, and includes at least one of: (i) inhibiting thedisease-state, i.e., partially or completely arresting its development;(ii) relieving the disease-state, i.e., causing regression of symptomsof the disease-state, or ameliorating a symptom of the disease; and(iii) reversal or regression of the disease-state, preferablyeliminating or curing of the disease. In a particular embodiment theterms “treating”, “treatment”, or the like, covers the treatment of adisease-state in a mammal, e.g., a primate, e.g., a human, and includesat least one of (i), (ii) and (iii) above. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by one of ordinary skill inthe art.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to theadministration of a compound provided herein to a subject, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of diseases or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Subjects with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, subjects who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.” In certain embodiments, the prevention isachieved by administration of a prophylactically effective amount of acompound of the invention.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a subject who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. The term “pharmaceutical composition” encompassescompositions containing a compound of the invention, e.g., crystal FormI or II, and a pharmaceutically acceptable carrier. A “pharmaceuticallyacceptable carrier” is a diluent, excipient or carrier that iscompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

II. Compounds of the Invention

In one embodiment, the invention provides crystalline Form I and Form IIof (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate having the following formula.

For clarity, the alpha-7 receptor agonist compound(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride was disclosed in United States Patent ApplicationPublication No. US 2005-0119325. However, in contrast to the presentinvention, such disclosure did not disclose or suggest the presentinvention,(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate, nor did it disclose any crystal forms of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate.

In one embodiment, the invention provides a crystalline Form I of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate, characterized by an x-ray powder diffractionpattern having peaks expressed as 2θ at one or both of 17.48 and20.58±0.20 degrees when measured against an internal silicon standard.

In another embodiment, the invention provides the crystalline Form I asdefined above, characterized by an x-ray powder diffraction patternfurther having at least one peak expressed as 2θ at 4.50, 9.04, 14.60,15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74, and 25.46±0.20 degreeswhen measured against an internal silicon standard.

In another embodiment, the invention includes the crystalline Form I asdefined above, characterized by an x-ray powder diffraction patternfurther having at least two peaks expressed as 2θ at 4.50, 9.04, 14.60,15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degreeswhen measured against an internal silicon standard.

In yet another embodiment, the invention provides the crystalline Form Ias defined above, characterized by an x-ray powder diffraction patternfurther having at least four peaks expressed as 2θ at 4.50, 9.04, 14.60,15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degreeswhen measured against an internal silicon standard.

The invention further includes the crystalline Form I as defined above,characterized by an x-ray powder diffraction pattern further having atleast six peaks expressed as 2θ at 4.50, 9.04, 14.60, 15.14, 15.80,16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degrees when measuredagainst an internal silicon standard.

The invention further includes the crystalline Form I as defined above,characterized by an x-ray powder diffraction pattern further having atleast eight peaks expressed as 2θ at 4.50, 9.04, 14.60, 15.14, 15.80,16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degrees when measuredagainst an internal silicon standard.

The invention further provides the crystalline Form I as defined above,characterized by an x-ray powder diffraction pattern further havingpeaks expressed as 2θ at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16,18.44, 19.48, 21.74 and 25.46±0.20 degrees when measured against aninternal silicon standard.

In another embodiment, the present invention provides a crystalline FormII of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate, characterized by an x-ray powder diffractionpattern having peaks expressed as 2θ at one or both of 21.16 and21.38±0.20 degrees when measured against an internal silicon standard.

In another embodiment, the present invention provides the crystallineForm II as defined above, characterized by an x-ray powder diffractionpattern further having at least one peak expressed as 2θ at 4.48, 9.00,13.58, 15.62, 16.48, 19.02, 19.44, 22.46 and 25.00±0.20 degrees whenmeasured against an internal silicon standard.

In yet another embodiment, provided herein is the crystalline Form II asdefined above, characterized by an x-ray powder diffraction patternfurther having at least two peaks expressed as 2θ at 4.48, 9.00, 13.58,15.62, 16.48, 19.02, 19.44, 22.46 and 25.00±0.2 degrees when measuredagainst an internal silicon standard.

In another embodiment, the present invention includes the crystallineForm II as defined above, characterized by an x-ray powder diffractionpattern further having at least four peaks expressed as 2θ at 4.48,9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46 and 25.00±0.2 degreeswhen measured against an internal silicon standard.

Further provided herein is the crystalline Form II as defined above,characterized by an x-ray powder diffraction pattern further having atleast six peaks expressed as 2θ at 4.48, 9.00, 13.58, 15.62, 16.48,19.02, 19.44, 22.46 and 25.00±0.2 degrees when measured against aninternal silicon standard.

Also provided here is the crystalline Form II as defined above,characterized by an x-ray powder diffraction pattern further having atleast eight peaks expressed as 2θ at 4.48, 9.00, 13.58, 15.62, 16.48,19.02, 19.44, 22.46 and 25.00±0.2 degrees when measured against aninternal silicon standard.

In another embodiment, provided herein is the crystalline Form II asdefined above, characterized by an x-ray powder diffraction patternfurther having peaks expressed as 2θ at 4.48, 9.00, 13.58, 15.62, 16.48,19.02, 19.44, 22.46 and 25.00±0.2 degrees when measured against aninternal silicon standard.

III. Methods of the Invention

A. Methods of Use

In an embodiment, the present invention provides the crystalline Form Ifor the treatment and/or prophylaxis of a disease which can be treatedor prevented by alpha-7 receptor activation. In another embodiment, thepresent invention provides crystalline Form II for the treatment and/orprophylaxis of a disease which can be treated or prevented by alpha-7receptor activation.

In another embodiment, the present invention provides a method oftreating or preventing a disease which can be treated or prevented byalpha-7 receptor activation comprising administering to a subjectcrystalline Form I. In another embodiment, a method of treating orpreventing a disease which can be treated or prevented by alpha-7receptor activation comprising administering to a subject crystallineForm II is provided.

In another embodiment, the present invention provides a method forimproving cognition or treating cognitive loss in a subject comprisingadministering to a subject the crystalline Form I. In anotherembodiment, the present invention provides the method for improvingcognition or treating cognitive loss by administering to a subject thecrystalline Form I wherein the subject is suffering from a disorderselected from: attention deficit disorder, attention deficithyperactivity disorder, and Parkinson's Disease. In another embodiment,the present invention provides the method for improving cognition ortreating cognitive loss by administering crystalline Form I wherein thesubject is suffering from a disorder selected from Alzheimer's Diseaseand schizophrenia.

In another embodiment, the present invention provides a method oftreating a disorder selected from attention deficit disorder, attentiondeficit hyperactivity disorder, Parkinson's Disease, Alzheimer's Diseaseand schizophrenia, the method comprising administering to a subject thecrystalline Form I. In another embodiment, the present inventionincludes a method of treating a subject that is at risk for developing adisorder selected from: Alzheimer's disease, Parkinson's Disease andschizophrenia, the method comprising administering to the subject thecrystalline Form I. In yet another embodiment, the present inventionincludes a method of treating a subject over age 60, comprisingadministering to the subject the crystalline Form I. In a furtherembodiment, the present invention includes a method of treating asubject for age-related memory loss, comprising administering to thesubject the crystalline Form I. In another embodiment the presentinvention includes a method of treating a subject for age-related memoryloss, comprising administering to the subject the crystalline Form Iwherein the subject is over age 60.

In another embodiment, the present invention provides a method forimproving cognition or treating cognitive loss in a subject comprisingadministering to a subject the crystalline Form II. In anotherembodiment, the present invention provides the method for improvingcognition or treating cognitive loss by administering crystalline FormII to a subject, wherein the subject is suffering from a disorderselected from: attention deficit disorder, attention deficithyperactivity disorder, and Parkinson's Disease. In another embodiment,the present invention provides the method for improving cognition ortreating cognitive loss by administering crystalline Form II to asubject, wherein the subject is suffering from a disorder selected fromAlzheimer's Disease and schizophrenia.

In another embodiment, the present invention provides a method oftreating a disorder selected from attention deficit disorder, attentiondeficit hyperactivity disorder, Parkinson's Disease, Alzheimer's Diseaseand schizophrenia, the method comprising administering to a subject thecrystalline Form II. In another embodiment, the present inventionincludes a method of treating a subject that is at risk for developing adisorder selected from: Alzheimer's disease, Parkinson's Disease andschizophrenia, the method comprising administering to the subject thecrystalline Form II. In yet another embodiment, the present inventionincludes a method of treating a subject over age 60, comprisingadministering to the subject the crystalline Form II. In a furtherembodiment, the present invention includes a method of treating asubject for age-related memory loss, comprising administering to thesubject the crystalline Form II. In another embodiment the presentinvention includes a method of treating a subject for age-related memoryloss, comprising administering to the subject the crystalline Form IIwherein the subject is over age 60.

B. Methods of Preparation

It would be beneficial to provide(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate in a stable crystalline form. After extensivestudies, two types of stable crystalline forms were identified: Form Iand Form II. One crystalline form does not convert to the other readilyin solid condition because each of two crystalline forms is stable. Onthe other hand, it was found that when one crystalline form wasdissolved in an aqueous solvent and the crystallization was carried outfrom the solution, it was difficult to predict which crystalline formwas preferentially produced. In addition, one form might be converted tothe other or a mixture of two forms quite easily in the solution undercertain conditions. Therefore the mechanism of crystallization wasunclear, and it was difficult to design methods for producing each format high purity. After extensive investigation, the inventors arrived atthe methods for selectively manufacturing each pure crystalline form.The methods can be carried out using a variety of different solvents.

A crystal form of a compound is usually obtained by: 1) dissolving thecompound in a solvent at a high temperature, where the solubility of theproduct is high, 2) lowering the temperature of the solution to causecrystallization of the compound, and 3) isolating the resultingcrystals.

However, solid state investigations revealed that there are twoenantiotropic crystalline forms of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate, and the present inventors discovered that theusual crystallization procedure is apt to produce a mixture of the twocrystal forms of the compound. This is because at higher temperatures,one crystal form of the compound is a little more stable in a solventsystem, whereas in at lower temperatures, the other crystal form of thecompound is a little more stable in the same solvent system. This effectcan be seen in Examples 5, 6, 7 and 8. Furthermore, the boundarytemperature for converting from one form to the other was found to varydepending on the solvent system in which the compound is dissolved.

The inventors extensively investigated the stable crystal forms atvarious temperatures and in various solvent systems and recognized thatForm I and Form II of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate can be separately prepared based on therelationship of temperature and water activity of the solventindependently of the particular organic solvent. This recognition led tothe creation of novel methods for separately manufacturing pure Form Iand pure Form II.

In an embodiment, the present invention provides a method for preparinga pharmaceutical composition, the method comprising combining thecrystalline form I with an excipient or pharmaceutically acceptablecarrier. In an embodiment, the method further includes combining thecrystalline form I with a liquid. In a further embodiment, the methodincludes filling a capsule with a composition comprising the crystallineform I.

In another embodiment, the present invention includes a method forpreparing a pharmaceutical composition comprising combining thecrystalline form II with an excipient or pharmaceutically acceptablecarrier. In an embodiment, the method further includes combining thecrystalline form II with a liquid. In a further embodiment, the methodincludes filling a capsule with a composition comprising the crystallineform II.

A method of manufacturing a crystalline Form I comprises: (1) stirring(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride (hereinafter,“(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride” includes any form of anhydrate, hydrate and solvate,preferably anhydrate and hydrate) in an aqueous organic solvent withinthe temperature-water activity range I, if required with decreasing thetemperature and/or water activity thereof, to form a substantially purecrystalline Form I; and (2) isolating the resulting crystalline Form I,wherein the temperature-water activity range I is defined by thefollowing relationship of the temperature and the water activity of theaqueous organic solvent, the water activity (x) of the aqueous organicsolvent is from 0.16 to 0.73; and the temperature (T) of the aqueousorganic solvent is higher than (183x−64.2) and lower than the boilingtemperature of the aqueous organic solvent.

In an embodiment, the method of manufacturing crystalline Form Iincludes a method where, in step (1) the initial state of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent is a solution, and thesolution is stirred within the temperature-water activity range I withdecreasing the temperature and/or water activity thereof. In anotherembodiment, the method of manufacturing crystalline Form I includes amethod where in step (1) the initial state of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent is a suspension, and thesuspension is stirred within the temperature-water activity range I, ifrequired with decreasing the temperature and/or water activity thereof.In a further embodiment, the method of manufacturing crystalline Form Iincludes a method where in step (1) the seed crystals of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride is added to the solution. In a still further embodiment,the method of manufacturing crystalline Form I includes a method wherethe seed crystals are Form I of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate.

In an embodiment the method of manufacturing crystalline Form I includesa method where the water activity is from 0.29 to 0.59. In anotherembodiment, the method of manufacturing crystalline Form I includes amethod where the temperature is between −10° C. and 60° C. and higherthan the following T: T=183x−57.6; wherein x is water activity of theaqueous organic solvent and T is a temperature (° C.). In yet anotherembodiment the method of manufacturing crystalline Form I includes amethod where the end point temperature in step (1) is between 0° C. and35° C.

In an embodiment, the method of manufacturing crystalline Form Iincludes a method where the aqueous organic solvent is mixture of waterand one or more of organic solvents which are miscible with water andare selected from alcohols, ketones, nitriles and ethers. In anotherembodiment, the method of manufacturing crystalline Form I includes amethod where the aqueous organic solvent is mixture of water and one ormore of organic solvents which are miscible with water and are selectedfrom propanol, butanol, butanone and acetonitrile.

The present invention also includes a method of manufacturing acrystalline Form II; comprising: (1) stirring(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent within the temperature-wateractivity range II, if required with decreasing the temperature and/orwater activity thereof, to form a crystalline Form II, and (2) isolatingthe resulting crystalline Form II, wherein the temperature-wateractivity range II is defined by the following relationship of thetemperature and the water activity of the aqueous organic solvent, thewater activity (x) of the aqueous organic solvent is from 0.16 to 0.73;and the temperature (T) of the aqueous organic solvent is lower than(183x−64.2) and higher than the freezing-point temperature of theaqueous organic solvent.

In an embodiment, the method of manufacturing crystalline Form IIincludes the method where in step (1) the initial state of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent is a solution, and thesolution is stirred within the temperature-water activity range II withdecreasing the temperature and/or water activity thereof. In anembodiment, the method of manufacturing crystalline Form II includes amethod wherein in step (1) the initial state of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent is a suspension, and thesuspension is stirred within the temperature-water activity range II,optionally decreasing the temperature and/or water activity thereof.

In another embodiment, the method of manufacturing crystalline Form IIincludes a method wherein in step (1) the seed crystals of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride is added to the solution. In yet another embodiment, themethod of manufacturing crystalline Form II includes a method whereinthe seed crystals are Form II of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate. In yet another embodiment, the method ofmanufacturing crystalline Form II includes a method wherein the wateractivity is from 0.29 to 0.59. In a further embodiment, the method ofmanufacturing crystalline Form II includes a method wherein thetemperature is between −10° C. and 60° C. and lower than the followingT: T=183x−70.8; wherein x is water activity of the aqueous organicsolvent and T is a temperature (° C.). In an embodiment, the method ofmanufacturing crystalline Form II includes a method wherein the endpoint temperature in step (1) is between 0° C. and 35° C. In anembodiment, the method of manufacturing crystalline Form II includes amethod wherein the aqueous organic solvent is mixture of water and oneor more of organic solvents which are miscible with water and areselected from alcohols, ketones, nitriles and ethers.

In another embodiment, the method of manufacturing crystalline Form IIincludes a method wherein the aqueous organic solvent is mixture ofwater and one or more of organic solvents which are miscible with waterand are selected from propanol, butanol, butanone and acetonitrile.

The present invention also provides another method for preparing thecrystalline Form I, comprising: (a) heating 10-30% by weight of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in acetonitrile or an aqueous acetonitrile to between 60°C. and the boiling point of the solution, (b) optionally adding water tothe mixture to fully dissolve the(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride; (c) cooling the solution until crystals are just visible;(d) if the water content is greater than 3% volume/volume when crystalsare just visible, adding acetonitrile to the mixture so that the watercontent is less than 3% volume/volume; (e) cooling the resulting mixtureto below 15° C.; and (f) isolating crystalline(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate.

In an embodiment, the method of preparing the crystalline Form Iincludes the method as defined in steps (a) through (f) above, whereinthe water added in step (a) does not bring the water content of themixture above 30% volume/volume. In another embodiment, the method ofpreparing the crystalline Form I includes the method as defined in steps(a) through (f) above, wherein(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride is present at 15-25% by weight in step (a). In anotherembodiment, the method of preparing the crystalline Form I includes themethod as defined in steps (a) through (f) above, wherein(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride is present at 16-20% by weight in step (a). In anotherembodiment, the method of preparing the crystalline Form I includes themethod as defined in steps (a) through (f) above, wherein(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride is present at 17-19% by weight in step (a). In yet anotherembodiment, the method of preparing the crystalline Form I includes themethod as defined in steps (a) through (f) above, further comprisingadding Form I(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate to the mixture after crystals are justvisible.

In yet another embodiment, the method of preparing the crystalline FormI includes the method as defined in steps (a) through (f) above, whereinstep (c) comprises cooling the solution to below 55° C. In yet anotherembodiment, the method of preparing the crystalline Form I includes themethod as defined in steps (a) through (f) above, wherein step (c)comprises cooling the solution to below 50° C.

Also included in the present invention is a method for preparing thecrystalline Form II, the method comprising: (a) heating 5-15% by weightof (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in 2-butanol or an aqueous 2-butanol to between 60° C. andthe boiling point of the solution; (b) if the water content is smallerthan 5% volume/volume, adding water to the mixture so that the watercontent is not less than 5% volume/volume; (c) cooling the solution tobelow 10° C.; (d) keeping the resulting mixture to below 10° C.; and (e)isolating crystalline(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate.

The present invention further includes a method for preparing thecrystalline Form II, the method comprising: (a) adding(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride to (i) acetonitrile or (ii) aqueous acetonitrile to createa composition that is 10-20% by weight of(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride; (b) optionally adding water to the composition to makethe water content 6-10%; (c) optionally cooling the solution at below10° C.; (d) allowing crystals to form; and (e) isolating crystalline(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate.

The crystalline Forms I and II are very stable in many aspects. Bothforms are stable under storage conditions. No degradation products fromeither form were detected under the storage conditions: 11% RH at 40°C., 75% RH at 40° C., 11% RH at 60° C. and 75% RH at 60° C. after 2weeks, and no degradation products from either form were detected underthe photo storage conditions: exposure to light (D65 lamp) of 1.2million Lux hours at 25° C. Both forms are also stable under physicalstress. The XRD charts of both forms were not changed after compressionexperiments with a planar pestle (1000 kgf/cm²).

The pure crystalline Forms I and II can be manufactured by the specialmethods, which are described herein.

Pure crystalline Form I can be manufactured by a method which comprises:(1) stirring(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent within the temperature-wateractivity range I (as depicted in FIG. 4), if required with decreasingthe temperature and/or water activity thereof, to form a substantiallypure crystalline Form I, and (2) isolating the resulting crystallineForm I.

Pure crystalline Form II can be manufactured by the method whichcomprises: (1) stirring(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride in an aqueous organic solvent within the temperature-wateractivity range II (as depicted in FIG. 4), if required with decreasingthe temperature and/or water activity thereof, to form a crystallineForm II, and (2) isolating the resulting crystalline Form II.

Water activity is a thermophysical coefficient used to represent theenergy status of the water in a system and is defined as the vaporpressure of water above a sample divided by that of pure water at thesame temperature. It can be measured with a capacitance hygrometer or adew point hygrometer. It can be also predicted by COSMO-RS method (FluidPhase Equililbria, 172 (2000) 43-72).

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride was prepared, for example, by the method described inWO03/55878. 7-Chloro-benzo[b]thiophene-2-carboxylic acid was reactedwith carbonyldiimidazole to give7-chloro-2-imidazolyl-carbonylbenzo[b]thiophene, followed by reactingwith (R)-3-aminoquinuclidine dihydrochloride to give(R)-7-chloro-N-(quinuclidin-3yl)benzo[b]thiophene-2-carboxamidehydrochloride.

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride used for the above manufacturing methods can be forexample crystals (e.g., Forms I, II, and mixtures thereof), amorphousproducts, an oil or a solution, and preferably a solution. Thecrystallization can be performed in the same vessel afterhydrochlorination. An aqueous organic solvent is a mixture of water andone or more organic solvents. The preferable organic solvents arewater-miscible organic solvents, and more preferable are for examplealcohols (e.g., C₁₋₆alkanol such as methanol, ethanol, 1-propanol,2-propanol, 1-butanol, 2-butanol, and C₂₋₆alkanediol such as ethyleneglycol, propylene glycol), ketones (e.g., C₃₋₆alkanone such as acetone,butanone), nitriles (e.g., acetonitrile, propanonitrile) and ethers(e.g. dimethoxyethane, tetrahydrofuran). Preferable solvents arealcohols, nitriles and ketones, and more preferable are propanols,butanols, butanone and acetonitrile.

In the present invention the solution is supersatured prior to theformation of crystals. The boundary between the temperature-wateractivity ranges for Forms I and II is shown in FIG. 4 as a line whichdivides the domains of Forms I and II.

Crystal forms may be monitored during the production method. Anyanalytical methods can be used for monitoring as long as it candistinguish crystal forms, and XRD is one of most preferable methods. Inorder to manufacture a pure form, stirring of the mixture is continueduntil undesired form completely converts to the desired form.

In the method for manufacturing Form I, Form X which is different fromboth Forms I and II may appear temporally, but Form X can be convertedto Form I and disappears if stirring of the mixture is continued.

IV. Pharmaceutical Compositions of the Invention

Provided also herein the present invention is a pharmaceuticalcomposition comprising the crystalline Form I. Also provided herein is apharmaceutical composition comprising the crystalline Form II.

The crystalline Forms I and II may be used to prepare a medicament totreat disease or condition in a mammal in need thereof, wherein mammalwould receive symptomatic relief from the administration of atherapeutically effective amount of a crystalline Form I or II. Thecrystalline Forms I and II may be administered in combination with othermedications for additive or synergistic therapeutic benefit for a givendisease. Diseases include, but are not limited to, those describedbelow. Medications include, but are not limited to, drugs which areapproved for a given indication e.g. acetylcholinesterase inhibitors forAlzheimer's Disease.

Because Form I is very stable and can be stored for a considerablelength of time prior to its use in the preparation of a drug product,Form I is useful in the manufacture of drug product even when themanufacturing process, i.e., the formulation of the active ingredient,causes some or all of the Form I to convert to another form.

The crystalline Forms I and II may be formulated as solutions orsuspensions, in the form of tablets, capsules (each including timedrelease and sustained release formulations), pills, oils, powders,granules, elixirs, tinctures, suspensions, syrups, emulsions,microemulsions, or with excipients. Likewise, they may also beadministered by any conventional route, for example in intravenous (bothbolus and infusion), intraperitoneal, intraocularly, subcutaneous,intramuscular form, enterally, preferably orally (e.g., in the form oftablets or capsules), or in a nasal, buccal, sub-lingual, transdermal,or a suppository form, using well known formulations to those ofordinary skill in the pharmaceutical arts. In addition, the crystallineForms I and II can be administered in the form of liposomes or the like.Disintegrators include, without limitation, delivery systems such assmall unilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

For oral administration in the form of a tablet or capsule, thecrystalline Forms I and II can be combined with an oral, non-toxicpharmaceutically acceptable inert carrier such as ethanol, glycerol,water and the like. Moreover, when desired or necessary, suitablebinders, lubricants, disintegrating agents and coloring agents can alsobe incorporated into the mixture. Suitable binders include starch,gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Suitable lubricants used in these dosage forms include, forexample, sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Suitabledisintegrating agents are, for example, starches, carboxymethylstarchsodium, crosscarmellose sodium and the like. Examples of the suitablecoloring agents are iron sesquioxide, yellow iron sesquioxide, amaranth,erythrosine, tartrazine, Sunset Yellow FCF and the like.

The dosage regimen for the crystalline Forms I and II is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

In one embodiment satisfactory results in animals are indicated to beobtained at a daily dosage of from about 0.1 to about 600 mg or fromabout 0.01 to about 5 mg/kg animal body weight.

Injected intravenous, subcutaneous or intramuscular dosages of thecrystalline Forms I and II, when used for the indicated effects, willrange between about 0.001 to 1.0 mg/kg. Furthermore, the crystallineForms I and II can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration can be continuous rather thanintermittent throughout the dosage regimen. Transdermal delivery canalso be achieved using approaches known to those skilled in the art.

Diseases that may be treated using the crystalline Forms I and IIinclude, but are not limited to: condition cognitive and attentiondeficit symptoms of Alzheimer's, neurodegeneration associated withdiseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosisattention deficit disorder, attention deficit hyperactivity disorder,mood and affective disorders, amytrophic lateral sclerosis, borderlinepersonality disorder, traumatic brain injury, behavioral and cognitiveproblems associated with brain tumors, AIDS dementia complex, dementiaassociated with Down's syndrome, dementia associated with Lewy Bodies,Huntingdon disease, depression, general anxiety disorder, age relatedmacular degeneration, Parkinson's disease, tardive dyskinesia, Pick'sdisease, post traumatic stress disorder, dysregulation of food intakeincluding bulimia and anorexia nervosa, withdrawal symptoms associatedwith smoking cessation and dependant drug cessation, Gilles de laTourette's Syndrome, glaucoma, neurodegeneration associated withglaucoma or symptoms associated with pain or is the treatment and/orprophylaxis for the improvement of perception, concentration, learningand/or memory.

EXEMPLIFICATION

The present invention is illustrated by the following examples, whichare not intended to be limiting in any way.

Example 1 Preparation of the Crystalline Form I

(R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride was synthesized by the procedure described in US2005-0119325. To prepare Form I, 1.0 Kg of the compound was dissolved inacetonitrile (5 L) and heated to 72-78° C. Once at this temperature,water (0.5 L) was added. The mixture was cooled to 50-60° C., whereincrystals are just visible and seed with Form I seed crystals. Themixture was held for a minimum of 2 hours, and then acetonitrile (20 L)was added while maintaining an internal temperature of 50-60° C. Thematerial was cooled to 5-10° C. Crystals were isolated by vacuumfiltration and washed with acetonitrile (2 L). The material was dried at40° C. in a vacuum oven with humidity control to provide 0.8 kg of pureForm I.

Example 2 Preparation of the Crystalline Form I

Acetonitrile (90 mL) and water (10 mL) were mixed at room temperature.1.0 ml of this solution was added to 100.7 mg of the crystalline Form Iof (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate. This suspension was stirred at 80° C. untilsolid component was dissolved, then the temperature was decreased to 40°C. for 80 minutes. During the cooling, spontaneous crystallization wasobserved round 52° C. To the suspension, 2.40 ml of acetonitrile wasdropped slowly, and then the temperature was decreased to 10° C. for 60minutes. The suspension was stirred at same temperature for 15 hours,and then the solid was filtered and washed with 0.20 ml of acetonitrile.After vacuum drying, 81.1 mg of the crystalline Form I was recovered.

Example 3 Preparation of the Crystalline Form II

Acetonitrile (90 mL) and water (10 mL) were mixed at room temperature.1.0 ml of this solution was added to 100.9 mg of the crystalline Form Iof (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate. This suspension was stirred at 80° C. untilsolid component was dissolved, then the temperature was decreased to 10°C. for 140 minutes. During the cooling, spontaneous crystallization wasobserved round 51° C. The suspension was stirred at same temperature for15 hours, then the solid was filtered and washed with 0.20 ml ofacetonitrile. After vacuum drying, 48.7 mg of the crystalline Form IIwas recovered.

Example 4 Preparation of the Crystalline Form II

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamidehydrochloride monohydrate (462 g) was triturated in 2308.5 mLacetonitrile and 230.85 mL of water at ambient temperature for 4.75hours. The producted was isolated by filtration and dried to afford 314g of isolated pure Form II.

Example 5 Phase Diagram in Aqueous Acetonitrile (1) SolubilityMeasurements of Forms I and II

Solubility of Forms I and II was measured at various temperaturesbetween 5° C. and 45° C. in aqueous acetonitrile in which waterconcentration was from 0 to 10 v/v % respectively.

Solubility was measured according to the following procedure. Form I orII crystals and an aqueous acetonitrile were added to a glass vessel.The mixture was stirred with a Teflon-coated magnetic stirrer bar at adefined temperature controlled with aluminum block. The liquid phase wassampled periodically, and the concentration of the compound was measuredwith high performance liquid chromatography (HPLC). Solid material wasalso collected at the same time to identify the crystal form using XRPD.In analyzing the time course of the change in concentration, thatplateau zone was identified as an equilibrium condition, and the meanvalue of these concentrations was defined as “solubility” under thatcondition. Measured solubility is summarized in Table 1.

TABLE 1 Results of the solubility measurement Conditions Water Stableform concentration Temp Solubility (Estimated from [v/v %] [° C.] Form IForm II Form X solubility) 0 5 1.0 * ** I 25 1.3 * ** I 2 5 2.4  2.6 **I 25 4.1  4.7 4.2 I 45 8.7 * 9.1 I 3.5 12.5 5.4  5.7 ** I 37.5 10.0 *10.3  I 6 5 12.8 11.2 ** II 25 17.1 16.7 ** II 45 27.2 29.6 ** I 8.512.5 27.6 25.1 ** II 37.5 44.4 44.4 ** I and II 10 5 * 29.7 ** II 2547.5 44.6 ** II 45 71.6 74.5 ** I * Could not measure ** Did not conduct(2) Solubility Equations were Modeled Using JMP 6 (SAS Institute)

With the response surface method, measured solubility values wereapplied to equation (1) to obtain solubility models as a function oftemperature and water concentration. W′ and T′ were defined as equations(2) and (3) respectively. Here, C*_(x), W and T mean solubility of acertain crystal form, water concentration in aqueous acetonitrile (v/v%) and temperature (° C.) respectively. Constant values from a, b, c, dand f were determined by applying measured solubility values with leastsquares fitting method within the range of 2 to 10 v/v % waterconcentration and within the range of 5 to 45° C. Perspective of defectsor accuracy, measured solubility values at 2%-45° C. of both forms,3.5%-37.5° C. of form II and 10%-10.0° C. of form I are excluded tobuild mathematical formulas.

C* _(x)=Exp(a+bW′+cT′+dW′T′+eW′ ² +fT′ ²)  (1)

W′=(W−6)/4  (2)

T′=(T−25)/20  (3)

Fitting results showed that constants were determined successfully, andthese models can describe solubility within the range with only minordeviation. Obtained solubility equations of Forms I and II are shown inequation (4) and (5) respectively.

C* _(I)=Exp(2.8448+1.2517W′+0.4185T′−0.1086W′T′−0.2249W′ ²+0.0681T′²)  (4)

C* _(II)=Exp(2.8389+1.1503W′+0.5101T′−0.0638W′T′−0.1888W′ ²+0.0488T′²)  (5)

(3) Development of Phase Diagram

Thermodynamic relationship between polymorphic crystal phases isconsistent with solubility. Based on the results of the solubilitymeasurements, it is apparent that thermodynamic relationship betweenforms I and II crystals is enantiotropy. Boundary of stable crystal formshould exist in the range that solubility measurement was carried out.At boundary condition, solubility of forms I and II should be same.Hence, boundary condition can be induced from equation (4) and (5) andsimplified as described in equation (6).

0.0059+0.1014W′−0.0916T′−0.0448W′T′−0.0361W′ ²+0.0193T′ ²=0  (6)

By solving boundary equation (6), boundary condition can be determined.Solved values are shown in Table 2. By plotting the results, phasediagram was described in FIG. 1. For convenience, this boundary linewhich obtained from equation (6) was fitted by fourth degree equation ofwater concentration. This approximation formula and its solved valuesare shown in equation (7) and Table 2 respectively.

T=0.0056W ⁴−0.1305W ³+0.2831W ²+11.3942W−31.3235  (7)

TABLE 2 Solved values of boundary equations Water concentrationTemperature[° C.] [% v/v] Equation (6) Equation (7) 3.0 2.34 2.34 3.57.26 7.27 4.0 11.86 11.86 4.5 16.08 16.09 5.0 19.91 19.91 5.5 23.3323.32 6.0 26.31 26.30 6.5 28.85 28.86 7.0 30.97 30.99 7.5 32.69 32.728.0 34.03 34.07 8.5 35.03 35.07 9.0 35.73 35.76 9.5 36.16 36.20 10.036.35 36.43

Example 6 Inter-Conversion Tests

Inter-conversion tests were also carried out in order to confirmreliability of obtained phase diagram of Example 5 (FIG. 1).

Solvent was added to a glass vessel and temperature was controlled withaluminum block. Identical amounts of Forms I and II crystals were addedto the vessel. The solutions were stirred for 13 to 40 hr withTeflon-coated magnetic stirrer bar. Solid component was sampled andanalyzed with XRPD to determine its crystal form.

The results were summarized in Table 3. These results were consistentwith phase diagram of Example 5.

TABLE 3 Experimental Results of Inter-conversion tests Temperature Waterconcentration run [° C.] [v/v %] Results 1 10 3.0 I 2 3.5 I 3 4.0 II 44.5 II 5 20 4.0 I 6 4.5 I 7 5.0 I 8 5.5 II 9 6.0 II 10 30 5.5 I 11 6.0 I12 6.5 I 13 7.0 I 14 7.5 II

Example 7 Crystallization Behavior in Aqueous Acetonitrile (1) Form X

Form X was found as another solid form in the solubility study. Atypical XRPD pattern of form X is shown in FIG. 2.

(2) Crystallization Behavior in 98 v/v % Aqueous Acetonitrile

Form I crystals were added to 98 v/v % aqueous acetonitrile in a glassvessel. Next, 98 v/v % aqueous acetonitrile was added to make themixture 40 v/w times relative to the Form I crystal. The mixture wasstirred with Teflon-coated magnetic stirrer bar and heated to 80° C.with aluminum block. After the crystals were dissolved, the mixture wascooled to a determined temperature at the rate of 30° C. per hour. Aftera determined holding time, Form I crystals were added as seed crystalsaccording to object of an experiment. Precipitates were sampledperiodically and analyzed by XRPD.

Initial precipitates in 98 v/v % aqueous acetonitrile system wereconfirmed as Form X. Spontaneous transformation from Form X to Form Iwas not observed within 16 hours. From the results of the seededexperiments, it was estimated that Form I is more stable than Form Xregardless of temperature. Form X could be recovered in 84.7% yield.

TABLE 4 Results of crystallization experiments in 98 v/v % aqueousacetonitrile Temperature Holding time Run [° C.] [hr] Crystal form 1 600 X 40 0 X 10 0 X 15 X Seeding* 2 X 8 X 27 X(I)** 2 60 0 X 40 0 X 16 XSeeding* 2 I + X 8 I 27 I 3 60 0 X 40 0 X 10 0 X 15 X — X *ca. 4% w/wForm I crystals **Slight amount of Form I was detected

(3) Transformation Behavior in 98 v/v % Aqueous Acetonitrile

Form I crystals and 40 v/w times volume of 98 v/v % aqueous acetonitrilewere added to a glass vessel. The mixture was stirred with Teflon-coatedmagnetic stirrer bar and heated to 80° C. with aluminum block. Afterdissolved, solution was cooled to 5° C. at the rate of 30° C. per hour.To the slurry of Form X, 10 w/w % of Form I crystals were added as seedcrystals at 5° C., then controlled to a certain temperature. Samples ofsolid material were analyzed by XRPD on a periodic basis.

Transformation from Form X to Form I was observed above ambienttemperature. This tendency to transform was also observed at 5° C. In 98v/v % aqueous acetonitrile system, it was estimated that Form I is morestable than Form X regardless of temperature though transformationkinetics was extremely slow at a low temperature.

TABLE 5 Results of transformation experiments in 98 v/v % aqueousacetonitrile Temperature Time Run [° C.] [hr] Crystal form 1 5  0* X 16X 40 X(I)** 2 25  0* X 16 I + X 40 I 3 40  0* X 16 I 40 I *Right afterthe seeding at 5° C. **Slight amount of Form I was detected(4) Transformation behavior in 97 v/v % aqueous acetonitrile

Form X crystals and 97 v/v % aqueous acetonitrile were added to a glassvessel. The mixture was stirred with Teflon-coated magnetic stirrer barat the temperature controlled with aluminum block. Solid component wassampled periodically and analyzed by XRPD to determine the crystal form.

Spontaneous transformation from Form X to Form I was observed in allexperiments. It was estimated that Form I is more stable than Form Xregardless of temperature in 97 v/v % aqueous acetonitrile.

TABLE 6 Results of transformation experiments in 97 v/v % aqueousacetonitrile Temperature Time Run [° C.] [hr] Crystal form 1 10 1 X 3 X21 I 2 20 1 X 3 X 21 I 3 30 1 X 3 I 21 I 4 40 1 X 3 I 21 I 5 50 1 I 3 I21 I

Example 8 Inter-Conversion Tests in Various Solvents

A mixture of crystalline Forms I and II (25 mg/25 mg) was stirred in 0.5mL of each organic solvent/water shown in Table 7 for 3 days at 5, 25,40 and 60° C., respectively, and the precipitates were filtrated, thenthe crystal forms were confirmed by XRPD. The results were shown in theTable 7.

TABLE 7 Results of inter-conversion tests in various solvents WaterConcentration Temperature[° C.] Solvent [v/v %] 5 25 40 60 2-Propanol 0I(II) I(II) I(II) I 2-Propanol 2 I(II) I I X 2-Propanol 5 I I I I2-Propanol 10 II I I sol 1-Propanol 0 I/X I/X I/II I/II 1-Propanol 2 I XI sol 1-Propanol 5 I I I(II) sol 1-Propanol 10 II sol sol sol Acetone 0I I/II I/X — Acetone 2 I I I — Acetone 5 I I I — Acetone 10 II I I —1-Butanol 0 I I I I 1-Butanol 2 I I I I 1-Butanol 5 II I I I 1-Butanol10 II sol Sol sol 2-Butanol 0 I I I I 2-Butanol 2 I I I I 2-Butanol 5 III I I 2-Butanol 10 II II II sol Acetonitrile 0 I/II I I I Acetonitrile 2I/II I I I Acetonitrile 5 II I I I Acetonitrile 10 II II I/II sol2-Butanone 0 I I/X I/X I/X 2-Butanone 2 II I I I 2-Butanone 5 II II II I2-Butanone 10 II sol sol sol I: form I II: form II I(II): form-I (smallamount of form-II) I/II: form-I/II mixture I/X: form-I/X mixture Sol:solution

Example 9 Relationship Between Water Concentrations and the Values ofWater Activity at Various Temperatures

The values of water activity of various water concentrations (i.e., 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 20 v/v %) in various organic solvents(i.e., 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone,2-butanone, and acetonitrile) at various temperatures (i.e., 0, 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55 and 60° C.), respectively, werecalculated using COSMOTHERME version 2.1 based on Cosmo-RS method.

The values of water concentrations (v/v %) were calculated on theboundary line (equation (6)) between Form I and Form II at varioustemperatures (i.e., 0, 5, 10, 15, 20, 25, 30, and 35° C.), and convertedinto the values of water activity using a regression curve of the cubicequation for plots of the values of water activity versus waterconcentrations at various temperatures (FIG. 3). Table 8 indicates therelationship between water contents (v/v %) and the values of wateractivity on the boundary line of the phase diagram. The values of wateractivity and the corresponding temperatures were fitted by equation (7)with a good correlation (correlation coefficient: 0.997).

T=183X−64.2  (7)

TABLE 8 Relationship between water concentrations (v/v %) and the valuesof water activity at various temperatures Temperature WaterConcentration [° C.] [V/V %] Water activity 0 2.77 0.349 5 3.27 0.382 103.79 0.411 15 4.37 0.437 20 5.01 0.460 25 5.77 0.483 30 6.76 0.509 358.48 0.551

The results of the inter-conversion tests were plotted and the boundaryline by equation (7) was drawn on the phase diagram of Form I and FormII as shown in FIG. 4. The boundary line approximately separated theForm I and Form II in all experimented solvent systems.

Example 10

Crystallization of Crystalline Form I

(1) 1-Propanol

Crystalline Form I (100.1 mg) was dissolved in 1 mL of 1-propanol/water(9:1(v/v)) at 70° C. The mixture was gradually cooled to 60° C. during20 minutes, and 1 mL of 1-propanol was added thereto. The mixture wasagain gradually cooled to 5° C. during 110 minutes with stirring. Then 3mL of 1-propanol was added thereto, and the mixture was stirred at 5° C.overnight. The crystals were isolated by filtration in vacuo and driedunder air at room temperature to give crystalline Form I (11.1 mg).

(2) 2-Propanol

Crystalline Form I (100.1 mg) was dissolved in 1 mL of 2-propanol/water(9:1(v/v)) at 90° C. The mixture was gradually cooled to 25° C. during130 minutes, and 1 mL of 2-propanol was added thereto. The mixture wasagain gradually cooled to 5° C., and 3 mL of 2-propanol was added. Themixture was stirred at 5° C. for 4 days. The crystals were isolated byfiltration in vacuo and dried under air at room temperature to givecrystalline Form I (48.9 mg).

(3) 1-Butanol

Crystalline Form I (100.0 mg) was dissolved in 1 mL of 1-butanol/water(9:1(v/v)) at 60° C., and 1 mL of 1-butanol was added thereto. Themixture was gradually cooled to 25° C. during 70 minutes, and 3 mL of1-butanol was added thereto. The mixture was again gradually cooled to5° C., and stirred at 5° C. overnight. The crystals were isolated byfiltration in vacuo and dried under air at room temperature to givecrystalline Form I (29.0 mg).

(4) 2-Butanol

Crystalline Form I (100.0 mg) was dissolved in 1 mL of 2-butanol/water(9:1(v/v)) at 90° C. The mixture was gradually cooled to 60° C. during60 minutes, and 1 mL of 2-butanol was added thereto. The mixture wasgradually cooled to 25° C. during 70 minutes, and 3 mL of 2-butanol wasadded thereto. The mixture was again gradually cooled to 5° C., andstirred at 5° C. overnight. The crystals were isolated by filtration invacuo and dried under air at room temperature to give crystalline Form I(52.1 mg).

(5) Acetone

Crystalline Form I (100.2 mg) was dissolved in 1.3 mL of acetone/water(9:1(v/v)) under reflux. The mixture was gradually cooled to 25° C.during 70 minutes, and 1.3 mL of acetone was added thereto. The mixturewas gradually cooled to 5° C., and 3.9 mL of acetone was added thereto.The mixture was stirred for 4 days at 5° C. The crystals were isolatedby filtration in vacuo and dried under air at room temperature, to givecrystalline Form I (74.5 mg).

(6) 2-Butanone

Crystalline Form I (100.3 mg) was dissolved in 1 ml of 2-butanone/water(9:1(v/v)) at 60° C. 4 mL of 2-butanone was added thereto. The mixturewas gradually cooled to 25° C. during 70 minutes, and the mixture wasstirred at room temperature for 4 days. The crystals were isolated byfiltration in vacuo and dried under air at room temperature to givecrystalline Form I (70.0 mg).

Example 11 Crystallization of Crystalline Form II (1) 1-Propanol

Crystalline Form I (100.0 mg) was dissolved in 1 mL of 1-propanol/water(9:1(v/v)) at 60° C. The mixture was gradually cooled to 5° C. during110 minutes, and was stirred for 4 days at 5° C. The crystals wereisolated by filtration in vacuo and dried under air at room temperatureto give crystalline Form II (11.0 mg).

(2) 2-Propanol

Crystalline Form I (100.3 mg) was dissolved in 1 mL of 2-propanol/water(9:1(v/v)) at 90° C. The mixture was gradually cooled to 5° C. during170 minutes, and was stirred for 5 days at 5° C. The crystals wereisolated by filtration in vacuo and dried under air at room temperatureto give crystalline Form II (40.2 mg).

(3) 1-Butanol

Crystalline Form I (100.1 mg) was dissolved in 1 mL of 1-butanol/water(9:1(v/v)) at 70° C. The mixture was gradually cooled to 5° C. during130 minutes, and 1 mL of 1-butanol was added thereto. The mixture wasstirred for 4 days at 5° C. The crystals were isolated by filtration invacuo and dried under air at room temperature to give crystalline FormII (31.6 mg).

(4) 2-Butanol

Crystalline Form I (100.2 mg) was dissolved in 1 mL of 2-butanol/water(9:1(v/v)) at 90° C. The mixture was gradually cooled to 5° C. during170 minutes, and 1 mL of 2-butanol was added thereto. The mixture wasstirred for 4 days at 5° C. The crystals were isolated by filtration invacuo and dried under air at room temperature to give crystalline FormII (54.7 mg).

(5) Acetone

Crystalline Form I (100.3 mg) was dissolved in 1.2 mL of acetone/water(9:1(v/v)) under reflux. The mixture was gradually cooled to 5° C. 110minutes, and 1 mL of acetone was added thereto. The mixture was stirredfor 4 days at 5° C. The crystals were isolated by filtration in vacuoand dried under air at room temperature to give crystalline Form II(36.4 mg).

(6) 2-Butanone

Crystalline Form I (100.2 mg) was dissolved in 1 mL of 2-butanone/water(9:1(v/v)) at 60° C. The mixture was cooled to 5° C. during 110 minutes.Next, 4 mL of 2-butanone was added thereto. The mixture was stirred for4 days at 5° C. The crystals were isolated by filtration in vacuo anddried under air at room temperature to give crystalline Form II (76.7mg).

Example 12 Physical Data of Forms I and II (1) Powder X-Ray Diffraction(XRD)

Diffraction patterns were taken at room temperature and humidity using aRigaku RINT-TTRIII diffractometer with Cu Kα radiation. The diffractionangle, 28, was scanned from 3 to 40 at rate of 2°/minute at a step sizeof 0.02°. The results of this analysis are shown in FIGS. 5 and 6, whichare the same as those measured against an internal silicon standard.

(2) Solubility

Excess amount of the samples, Forms I and II, were suspended in water,and were equilibrated by shaking for 20 minutes at 25° C. or 37° C.,respectively. The amounts of dissolved the compound were determinedusing a Waters alliance HPLC system 2695, detected by UV 210 nm. Theresults of this analysis are shown in Table 9.

TABLE 9 Solubility in water of the crystalline Forms I and IITemperature Form I Form II 25° C. 39 mg/mL 30 mg/mL 37° C. 90 mg/mL 54mg/mL

(3) Hygroscopicity

The hygroscopicity of Forms I and II were investigated using a Surfacemeasurement systems, DVS-1, between 10% RH and 90% RH at 25° C. Therewas no hygroscopicity in Form I. On the other hand, there was ahygroscopicity in Form II, and the water value of approximately 4% wasincreased and decreased between 10% RH and 90% RH by absorption anddesorption of ca. 1 mol of channel water.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents were consideredto be within the scope of this invention and are covered by thefollowing claims. Moreover, any numerical or alphabetical rangesprovided herein are intended to include both the upper and lower valueof those ranges. In addition, any listing or grouping is intended, atleast in one embodiment, to represent a shorthand or convenient mannerof listing independent embodiments; as such, each member of the listshould be considered a separate embodiment.

1-72. (canceled)
 73. A method of treating a patient in need thereof, comprising administering to the patient a crystalline Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.
 74. The method of claim 73, wherein the crystalline Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate is characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ at: i) one or both of 17.48 and 20.58±0.20 degrees when measured against an internal silicon standard; and ii) at least four peaks selected from a group of peaks consisting of: 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degrees when measured against an internal silicon standard.
 75. The method of claim 74, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with at least six peaks selected from the group of peaks.
 76. The method of claim 74, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with at least eight peaks selected from the group of peaks.
 77. The method of claim 74, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with all of the peaks selected from the group of peaks.
 78. The method of claim 73, wherein the method improves cognition or treats cognitive loss in the patient.
 79. The method of claim 78, wherein the patient suffers from a disorder selected from: attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson's Disease.
 80. The method of claim 78, wherein the patient suffers from a disorder selected from Alzheimer's Disease and schizophrenia.
 81. The method of claim 80, wherein the method improves cognition in the patient suffering from Alzheimer's Disease.
 82. The method of claim 80, wherein the method improves cognition in the patient suffering from schizophrenia.
 83. The method of claim 80, wherein the method treats cognitive loss in the patient suffering from Alzheimer's Disease.
 84. The method of claim 80, wherein the method treats cognitive loss in the patient suffering from schizophrenia.
 85. The method of claim 78, wherein the patient is at risk for developing a disorder selected from: Alzheimer's disease, Parkinson's Disease and schizophrenia.
 86. The method of claim 78, wherein the patient is over age
 60. 87. The method of claim 78, wherein the patient suffers from age-related memory loss.
 88. A method of treating a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a crystalline Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.
 89. The method of claim 88, wherein the crystalline Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate is characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ at: i) one or both of 17.48 and 20.58±0.20 degrees when measured against an internal silicon standard; and ii) at least four peaks selected from a group of peaks consisting of: 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±0.20 degrees when measured against an internal silicon standard.
 90. The method of claim 89, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with at least six peaks selected from the group of peaks.
 91. The method of claim 89, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with at least eight peaks selected from the group of peaks.
 92. The method of claim 89, wherein the crystalline Form I is characterized by an x-ray powder diffraction pattern with all of the peaks selected from the group of peaks.
 93. The method of claim 88, wherein the method improves cognition or treats cognitive loss in the patient.
 94. The method of claim 93, wherein the patient suffers from a disorder selected from: attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson's Disease.
 95. The method of claim 93, wherein the patient suffers from a disorder selected from Alzheimer's Disease and schizophrenia.
 96. The method of claim 95, wherein the method improves cognition in the patient suffering from Alzheimer's Disease.
 97. The method of claim 95, wherein the method improves cognition in the patient suffering from schizophrenia.
 98. The method of claim 95, wherein the method treats cognitive loss in the patient suffering from Alzheimer's Disease.
 99. The method of claim 95, wherein the method treats cognitive loss in the patient suffering from schizophrenia.
 100. The method of claim 93, wherein the patient is at risk for developing a disorder selected from: Alzheimer's disease, Parkinson's Disease and schizophrenia.
 101. The method of claim 93, wherein the patient is over age
 60. 102. The method of claim 93, wherein the patient suffers from age-related memory loss. 